Off-target genomic DNA loci (Apolipoprotein C-III sgRNA) (APOC3 off-targets)

Off-target genomic DNA loci with partial complementarity to the APOC3 sgRNA represent unintended sites of genetic modification during CRISPR-based therapeutic interventions targeting the Apolipoprotein C-III (APOC3) gene (Verve Therapeutics, 2023). These loci are characterized by DNA sequences that closely resemble the 20-nucleotide target sequence of the sgRNA, allowing the Cas enzyme or base editor complex to bind and induce changes, provided a compatible Protospacer Adjacent Motif (PAM) is adjacent (Fu et al., 2013). In the context of drugs like VERVE-201, which utilizes base editing to lower triglyceride levels, these off-target sites are not therapeutic targets but rather safety risks that must be rigorously characterized (Tsai et al., 2015). Unintended edits at these locations can lead to deleterious effects such as gene disruption, chromosomal translocations, or the activation of proto-oncogenes, potentially resulting in long-term toxicities or secondary malignancies (Kosicki et al., 2018). Consequently, identifying and minimizing activity at these loci is a primary focus of genomic medicine safety assessments and regulatory filings for CRISPR-based therapies.

Other names

CRISPR off-target sitesNon-specific genomic binding sitessgRNA-APOC3 off-targetsUnintended APOC3 editing sites

Unintended DNA modification (cleavage or base editing) at non-target genomic sites due to sequence homology with the guide RNA.